Download 6 Gastrointestinal System, Obesity, and Body Composition

6
Gastrointestinal System, Obesity,
and Body Composition
Ann O. Scheimann, Phillip D.K. Lee, and Kenneth J. Ellis
Obesity or overweight is arguably the most obvious physical feature
of PWS. Perhaps for this reason, more than 80% of the over 1,600 publications to date regarding PWS mention, discuss, and/or explore the
topic of obesity. Despite this attention, the diagnosis, pathogenesis,
optimal treatment, monitoring, and outcome of this condition in PWS
remain undefined. In addition, the paradox of the underweight infant
with PWS evolving into an overweight child and adult has led to considerable speculation regarding pathophysiology.
In addition to the obvious physical feature of obesity/overweight
and questions regarding optimal nutritional management, a variety of
gastrointestinal (GI) disorders have been identified in PWS, with frequencies similar to respiratory disorders. A description of the GI system
and related disorders in PWS will start this chapter, followed by a discussion of obesity and related nutrition and medical issues. Finally, a
discussion of analytical methods for body composition analysis and
their application in PWS is presented (see Chapter 5 for a complete
outline of Part II).
Gastrointestinal System and Disorders
The primary function of the gastrointestinal system is to facilitate
intake, digestion and absorption of nutrients. The elements of the
system and their functions are as follows:
1. Oropharynx and Esophagus: sucking, mastication (chewing and
softening of food), salivation, swallowing (deglutition), transfer of
food to the stomach
2. Stomach and Intestines: digestion, production of regulatory hormones, absorption of nutrients and elimination of waste
Elements of these processes may be relevant to the pathophysiology
of PWS. Therefore, each of the following sections begins with a very
brief description of the relevant physiology, followed by a review of
PWS-related pathophysiology and treatment.
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Oropharynx
Physiology
In the resting state, in which a person is not eating or vocalizing, the
oral cavity undergoes continual involuntary salivation and swallowing. Saliva is derived primarily from the parotid, submandibular, and
sublingual glands in the oral cavity (90%); another 10% is derived from
scattered salivary glands. An average adult produces 0.5 to 1.5 L per
day. Saliva is composed primarily of water with dissolved proteins,
enzymes, and minerals; the composition differs according to the source
gland. The major functions of saliva include lubrication and cleansing
of the oral cavity, neutralization of acids, inhibition of microbial growth,
and protection of dentition.133,157
Taste, smell, and palatability are among the initial food qualities that
determine intake and retention of substances in the oral cavity. After
entry of solid or semisolid food into the oral cavity, a complex neuromuscular process of chewing (mastication), salivation, and swallowing
(deglutition) follows. In the neonatal period, ingestion of liquid substances normally involves primarily deglutition (without mastication),
and the physical mechanisms differ somewhat from that which occurs
with solid food ingestion.
Mastication combines a number of processes, including reduction of
food to smaller pieces suitable for deglutition. The teeth serve as passive
tools for this process and are controlled by coordinated activity of the
powerful jaw muscles.102,187 The muscles of the tongue participate in
churning and mixing of food in the oral cavity and movement of food
toward the esophagus. Coordinated movement of the jaw, laryngeal,
and pharyngeal muscles occurs both voluntarily and involuntarily,
with neurosensory input and feedback.119 Mastication may also play a
role in feedback regulation of appetite,163 although this has yet to be
demonstrated in humans.
Increased salivation occurs in anticipation of food intake (e.g., via
visual and olfactory inputs), during taste (gustatory stimulus), and
during mastication. The neural inputs for this process have been summarized.157 Gustatory input via cranial nerves VII (facial), IX (glossopharyngeal), and X (vagus) and masticatory input via cranial nerve V
(trigeminal) to the brainstem salivary center is then relayed back to the
salivary glands via cranial nerves VII (to the submandibular and sublingual glands) and IX (to the parotid glands), resulting in increased
salivation. The stimulated parotid gland, which produces an amylaserich saliva, can reach 50% of total production during mastication.
During mastication, saliva has key roles in enhancing taste perception,
solubilizing food products, initiation of starch and lipid digestion, and
preparation of food boluses for swallowing.
The process of swallowing starts with movement of processed food
toward the back of the oral cavity, accomplished primarily by voluntary movement of the tongue. The second stage involves a reflex elevation of the pharynx and peristaltic movement of the food into the
esophagus. The larynx also elevates, with closure of the epiglottis,
thereby protecting the airway during swallowing.171 The final stage of
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
swallowing involves anterograde esophageal peristalsis, resulting in
movement of the food bolus into the stomach. Swallowing is mediated
by input via cranial nerves IX and X to the brainstem swallowing
center, with output via cranial nerves V, VII, IX, X, and XII.64,157 The
entire process of swallowing is facilitated by saliva, which provides the
necessary lubrication. In addition, saliva buffers the oropharynx and
esophagus against acidic food and back leakage of gastric acid.
The human neonate relies exclusively upon the sucking reflex for
nutrient ingestion.70 The suck reflex develops relatively early during
fetal life and involves intra- and peri-oral stimulation, leading to activation of brainstem centers interacting with the motor cortex, leading
to rhythmic motor activity mediated by cranial nerves V, VII, and XII.
Nonnutritive sucking (e.g., use of a pacifier) may have somewhat different dynamics and regulation from nutritive sucking (i.e., breast- or
bottle-feeding),70 the latter presumably involving additional coordination with swallowing. Although a sucking motor pattern can be identified in the 10- to 12-weeks’ gestation fetus, coordination of sucking,
swallowing, and respiration does not occur until after 35 weeks.89,144 As
with oral food intake after the neonatal period, the suck reflex is highly
dependent upon oropharyngeal muscle tone and function.
Pathology in PWS
Generalized hypotonia in the neonate with PWS is manifested by an
extremely weak suck reflex, lacking in both strength and endurance.87
In addition, apparent lack of coordination between suck/swallow and
breathing has been anecdotally observed in some infants. Although not
yet studied in detail, hypotonia of the laryngeal, pharyngeal, and
esophageal musculature could lead to further problems with swallowing, airway protection, and efficient movement and retention of liquid
in the stomach.
Although the oropharyngeal hypotonia usually improves sufficiently
to allow adequate oral nutrition by 6 to 12 months of age, the underlying problem probably continues throughout the life span. Older individuals with PWS are often noted to avoid meat and other foods that
require a relatively high oromotor effort, which may in part account
for the noted preference for carbohydrates over protein.69 Micrognathia
and microdontia (small lower jaw and teeth), noted in some individuals with PWS, may further compound the problem by providing less
muscle bulk and surface area.
Perhaps even more problematic is the lack of adequate salivation.
Unusually viscous saliva has been noted in the majority of patients
with PWS,22,105 and decreased volume of saliva is virtually universal.
Saliva collection and analysis from 25 individuals with PWS (1 to 53
years old) showed an unstimulated salivary flow rate of 0.16 g/min,
as compared with 0.54 g/min in controls.94 Stimulation of salivary flow
by mastication of paraffin increased the flow to only 0.38 g/min, as
compared with 2.38 g/min in controls (it should also be noted that
saliva could not be collected from an additional 15 PWS subjects
due to inadequate flow and/or viscosity). PWS saliva was noted to
be extremely viscous, with increased concentrations of all measured
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solutes, including fluoride (165%), calcium (226%), phosphorous
(157%), chloride (124%), sodium (154%), and protein (126%). No differences were noted between the 3 uniparental disomy and 17 deletion
subjects (5 did not have detailed genetic studies). A similar, but not
entirely identical, condition of decreased salivation and hyperconcentration of salivary fluid has been noted in non-PWS patients with
denervation of the parotid gland.130 However, a normal but prominent
appearance of the three major salivary glands, despite decreased salivation, was noted in one subject with PWS.204
Decreased salivary secretion, or xerostomia (“dry mouth”), leads to
decreased natural cleansing of the oral cavity, severe dental caries,
enamel erosion, infection, and tooth loss.7,11,94 These disorders are
similar to those observed with xerostomia associated with other conditions.133 Enamel erosion is due to inadequate salivary buffering of foodderived acids from citrus, acidic substances (including carbonated
sodas, both regular and diet), and bacterial metabolism of dietary sugar
and starch,18,204 resulting in resorption of bone mineral in the acidic
milieu.
In non-PWS patients, xerostomia has been associated with speech
abnormalities (dysphonia), a sensation of thirst resulting in frequent
sipping, oral discomfort, difficulty with mastication and swallowing,
taste disturbances (dysgeusia), heartburn, and halitosis.133,157 Several of
these features are also noted in PWS, although direct cause/effect relationships have not been systematically studied.
Treatment
In neonates with PWS, hypotonic suck and lack of a coordinated feeding
mechanism can often lead to a severe failure-to-thrive. Nasogastric
tube-feeding is often used to meet nutritional needs,79 and many infants
require gastrostomy tube placement to facilitate feeding for the first
few months of life.
The use of treatment strategies to improve oromotor strength and
coordination of swallowing can significantly enhance feeding success.
Such strategies may include early introduction of occupational and
speech therapies, use of adaptive devices, positioning strategies, jawstrengthening exercises, thickening agents for liquids, and use of lowcalorie binding agents. These therapies reduce the need for parenteral
(tube) feedings, as shown by our experience at Texas Children’s Hospital (Figure 6.1). Infants with PWS who received supplemental oromotor therapy required nasogastric feedings for a mean of 40 days, as
compared with 234 days for infants who did not receive this therapy
(p = 0.003).
Occupational and speech therapy are often utilized after the neonatal
period (see separate chapters); the efficacy of these treatments in relation to feeding behavior and food preferences has not been studied in
PWS, and there is poor documentation of results in other forms of
dysphagia associated with muscle disease.101 Nonetheless, these therapies are generally recommended for individuals with PWS.
Nonpharmacologic treatment of xerostomia in non-PWS patients
often involves the use of natural secretagogues (e.g., sour lozenges,
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
Figure 6.1. Impact of supplemental therapies on the duration of nasogastric
tube feedings in infants with PWS (total N = 15). The y-axis is the mean number
of days that nasogastric feedings were required. The x-axis shows supplemental therapies that were administered. (Source: A. Scheimann, unpublished
data.)
sugarless chewing gum) to provide continuous salivary gland stimulation. This approach has been reported in some individuals with PWS,204
but larger scale studies have not been conducted. Pharmacologic treatment of xerostomia has relied primarily upon topical application of
artificial saliva, although the use of salivary secretagogues is increasing161; these modalities have not been studied in PWS.
Given the high risks for severe dental caries and infection, regular
dental care must be established for all individuals with PWS. Oral
hygiene should be instituted in infancy, even if dental eruption has not
yet occurred, using soft foam toothbrushes and wetting solutions. This
may be particularly important for infants on parenteral feedings, where
there is virtually no stimulation of salivation or wetting from oral feeds.
Fluoride treatment may also be recommended. For treatment of caries,
adhesive dental techniques have been recommended.18
Avoidance of sugars, thick starchy foods, citrus, carbonated drinks,
and other acidic foods is advisable. In addition, individuals with PWS
should be encouraged to include copious amounts of water with each
meal to facilitate mastication, swallowing, and oral cleansing.
Stomach and Intestines
Physiology50
After swallowing, esophageal peristalsis results in delivery of food
boluses into the antrum of the stomach. In the resting condition, the
lower esophageal sphincter, composed of specialized smooth muscle
cells (not a true sphincter) maintains a positive pressure to prevent
gastric contents from moving back into the esophagus. During swallowing, this pressure is released in response to local stimuli, including
vasoactive intestinal peptide (VIP) and nitric oxide, thereby allowing
food to enter the antrum of the stomach.
The stomach, which begins at the lower esophageal sphincter
and ends at the pyloric sphincter, is composed of inner circular and
outer longitudinal layers of smooth muscle which undergo rhythmic
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contractions controlled by a pacemaker located in the main portion of
the stomach. The stomach is lined by secretory cells, including parietal,
chief, and mucus cells. In response to food-related stimuli (smell, visual,
cerebral), the vagus nerve signals release of acid from the parietal cells;
this effect is mediated by histamine and gastrin. The acid environment,
in turn, inhibits further gastrin release and also stimulates local production of somatostatin, which inhibits histamine and gastrin release. The
parietal cells also produce intrinsic factor, which is required for absorption of vitamin B12.
Vagal stimulation also results in release of pepsinogen from the chief
cells of the stomach. In the presence of gastric acid, pepsinogen is processed to pepsin, which is the major enzyme involved in the initial
steps of protein digestion.
Neurons within the stomach produce a number of substances that
participate in regulation of gastrin, histamine, acid, and somatostatin
release. These include acetylcholine and calcitonin gene-related peptide
from the vagus nerve and pituitary adenylate cyclase-activating
peptide, VIP, gastrin-releasing peptide, galanin, and nitric oxide from
enteric neurons. Some of these peptides are also postulated to affect
normal eating behavior and are discussed in the section on obesity.
When liquid substances enter the stomach, vagal stimulation results
in relaxation of the proximal stomach, where the liquid is retained until
gastric emptying. Solid foods are mixed, digested, and reduced to small
particles in the distal stomach. Gastric emptying is accomplished by
both muscular contractions of the stomach and by alternate opening
and closure of the pyloric sphincter, which is under sympathetic and
vagal control, respectively.
After passing through the pyloric sphincter, partially digested material enters the duodenum, where the fat, protein, and gastric acid
stimulate duodenal production of cholecystokinin (CCK) and secretin.
These peptides are absorbed into the bloodstream and travel to the
pancreas, activating vagal stimulation of pancreatic enzyme secretion
into the intestinal lumen. Duodenal distention also leads to pancreatic
enzyme secretion through direct vagal stimulation (enteropancreatic
reflex). These enzymes include (1) pancreatic amylase, which digests
carbohydrates to oligosaccharides; (2) lipase and colipase, which digest
fat (triglycerides) to monoglycerides and fatty acids; and (3) trypsin,
chymotrypsin, and elastase, which digest peptides (resulting from
pepsin digestion of proteins in the stomach) to oligopeptides.
Further digestion into amino acids, fatty acids, monoglycerides, and
monosaccharides occurs in the small intestine. These nutrients are
absorbed into the bloodstream from the intestinal lumen. In addition,
the small and large intestines are responsible for absorption of water
and electrolytes. Finally, the large intestine and anal sphincter are
responsible for the process of solid waste elimination, or defecation.
A number of peptides are released from the gastrointestinal tract and
pancreas into the bloodstream during the process of food intake, digestion, and absorption. These include insulin, glucagon, and postulated
appetite-regulatory hormones. Some of these peptides are discussed in
the section on obesity.
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
Pathology and Treatment in PWS
Retrograde Movement of Ingested Substances: Normally, ingested nutrients move in an anterograde (forward) fashion from the mouth to
stomach to intestines with minimal backflow. Retrograde movement of
food from the stomach into the oropharynx may occur under two
primary circumstances: (1) gastroesophageal reflux and (2) emesis. Voluntary regurgitation and reprocessing of food from the stomach, or
rumination, may also occur. Retrograde movement of intestinal contents has been observed in cases of severe obstruction and constipation
in patients without PWS, but these problems have not been reported
to be a particular concern in PWS.
Gastroesophageal reflux is a passive phenomenon in which liquid
and partially digested food moves up the esophagus from the stomach
into the oropharynx. Gastroesophageal reflux is a relatively common
finding in otherwise normal (non-PWS) infants, occurring in the
majority of infants under 4 months of age153 and usually resolving
within the first year of life.190 The severity may be increased in infants
with hypotonia, prematurity, or other predisposing conditions. Contributory factors may include transient relaxation of the lower esophageal sphincter pressure and positioning after feeds. It has been
postulated that reflux may trigger arousal, thereby being protective
against sudden death in infants.190 In addition, in non-PWS infants, it
has been found that a nasogastric tube increases the frequency of reflux
episodes.160
In severe cases, chronic reflux of gastric acid can cause esophagitis,
esophageal stricture, and cellular dysplasia and carcinoma of the distal
esophagus. In older children and adults, gastroesophageal reflux may
be associated with symptoms of “acid reflux” or heartburn. Endoscopic
evaluation and surgical treatment may be necessary.
Possible gastroesophageal reflux has been occasionally reported in
PWS,18 but systematic documentation of prevalence has not been performed. Anecdotal experience suggests that clinically significant reflux
is not as commonly observed in infants with PWS as might be expected.
In addition, typical symptoms and complications due to gastroesophageal reflux have not been reported. This may, in part, be due to the
lower volumes per oral feed that are usually ingested by PWS infants.
There are concerns regarding the possibility that due to hypotonia,
infants with PWS may be unable to adequately protect the airway
during reflux episodes, thereby increasing the risks for aspiration
pneumonia and respiratory compromise. As a safety measure, reflux
precautions should be taken for all infants with PWS, especially if
taking substantial volumes of oral bolus feeds, and continued until the
child is ambulatory. Optimal precautions have not, however, been
defined in infants with PWS. In non-PWS infants, a 30-degree incline
post feeds (e.g., in an infant seat) has been traditionally recommended.
Given the concerns that this may worsen reflux in some infants due to
increased intra-abdominal pressure, the prone or left-lateral position
has been recommended,160,190 but the relative advantages of this
positioning have not been tested in infants with PWS. In any case, a
supine position should be avoided.
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Gastroesophageal reflux and/or complications related to this
condition have not been reported in older individuals with PWS. Since
individuals with PWS have decreased pain sensation (see Chapter 5),
typical symptoms of heartburn may not be a reliable indicator of
acid reflux. In one case of a 27-year-old man with PWS, heartburn
was reported, but no abnormalities were noted on endoscopic
examination.204
Emesis is an active process that may be considered to be a normal
protective reflex. When emetic agents and toxins enter the gastrointestinal lumen, mucosal chemoreceptors are triggered which then signal
through the vagus nerve back to a brainstem emetic center.107 Emetic
toxins in the bloodstream signal directly to this same area through the
area postrema of the brainstem. Processing of these signals results in
sequential signaling through vagal and other motor neurons, resulting
in retching (simultaneous, forceful contractions of the diaphragm and
abdominal muscles) and expulsion (prolonged forceful contraction of
the abdominal muscles in coordination with the rib cage and pharyngeal and laryngeal muscles). Retrograde intestinal contraction occurs
with gastric relaxation. Emesis then results from sequential and coordinated increases in intra-abdominal and intrathoracic pressure. Active
retrograde peristalsis of the stomach or esophagus is not thought to be
involved in emesis. Hypothalamic release of vasopressin and oxytocin
may also be essential elements of emesis.
A commonly reported feature of PWS is a decreased ability to vomit,
with a complete absence of “natural” or induced (e.g., with syrup of
ipecac) vomiting noted in a large proportion of individuals.3,104 The
reasons for this are not completely known. Hypotonia of the diaphragmatic, abdominal, and intercostal muscles may be contributory since
forceful contractions of these muscles are required for emesis. A deficiency of oxytocin neurons179 could play a role, although CSF oxytocin
levels are reportedly elevated in PWS.140 Vagal autonomic dysfunction
is also a possibility, although, as reviewed in Chapter 5, the evidence
for autonomic dysfunction in PWS is limited.
Caution has been advised regarding reliance on emetic agents,
particularly syrup of ipecac, in the treatment of accidental poisoning
for individuals with PWS since the response may be inadequate. The
American Academy of Pediatrics no longer recommends routine supply
or use of syrup of ipecac for home treatment of childhood ingestion46;
therefore, this issue may be a moot point, at least in the U.S. Instead,
parents and guardians are advised to call the local poison control center
for guidance. However, healthcare practitioners and guardians should
be aware of the decreased ability to vomit in the event that an emetic
therapy is considered in the emergency room or other medical care
facility.
Although most individuals with PWS have a decreased ability to
vomit, others may have rumination, a condition characterized by voluntary regurgitation of gastric contents that are then rechewed and
reswallowed. A survey study found that 10% to 17% of 313 individuals
with PWS reported a history of rumination and that approximately half
of this group had a history of emesis.3 Rumination was also suspected
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
in a 17-year-old who was found to have gastric secretions in her pharynx
despite fasting during preparation for general anesthesia.174 Rumination may be a form of self-stimulation and, in the case of PWS, a means
of obtaining food, albeit reprocessed.
Regurgitated food usually contains gastric acid, which may add to
problems with dental enamel erosion. Therefore, in addition to behavioral treatment, the use of pharmacologic agents to block stomach acid
secretion should be considered in patients who have rumination.
Gastric Dilatation: In 1997, Wharton et al.197 reported six females with
massive gastric dilatation; two died of gastric necrosis, one died of
cardiac arrest, and three survived. Fever, abdominal pain, and distention were presenting signs, and vomiting was reported in two cases.
These individuals had all had strict dietary control; the authors postulated that gastric muscular atony and atrophy may have occurred
as a result of the dietary limitations, resulting in dilatation and necrosis following sudden ingestion of a large quantity of food. No
additional cases have been published and the prevalence of this condition in PWS is unknown. However, aside from the usual recommendations for prevention of binge eating, caretakers should be vigilant
for signs of acute onset of unusual abdominal distention, fever, and
emesis.
Bowel Complaints: As indicated in Figure 6.2, complaints related to
bowel function are frequently reported by individuals with PWS (data
summarized from various sources). For the most part, these appear to
Figure 6.2. Symptom prevalence in adults with PWS (Sources: Butler et al.,27
2002, Holm et al.,104 1992, and personal communications from S.B. Cassidy and
B.Y. Whitman.)
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be secondary to factors related to eating. As of this writing, no intrinsic
abnormalities in bowel anatomy or function have been associated with
PWS.
Composite data indicate that 20% of individuals with PWS report
constipation. Constipation can be defined as hard, dry bowel movements, usually occurring less than three times a week. Abdominal and
rectal pain, rectal fissures, hemorrhoids, and rectal bleeding (bright red
blood) may occur in association with the disordered defecation. In
addition, affected individuals may have abdominal distention, bloating, and a general feeling of discomfort. Lack of dietary fiber and
inadequate liquid ingestion may be contributory factors. Hypotonia of
the pelvic floor and abdominal muscles can increase the difficulty of
defecation. General physical immobility is also associated with constipation. Although hypothyroidism does not occur with increased frequency in PWS, it is fairly common in the general population and often
presents with constipation.
Treatment of constipation involves provision of adequate dietary
water and fiber, encouragement of physical activity, and thyroid
hormone replacement, if deficient. In some cases, rectal stimulation,
irrigation, suppositories, or enemas may be necessary to clear the rectal
ampulla. Laxatives may be helpful in some cases; however, chronic use
is not recommended.
Diarrhea, often thought of as the opposite of constipation, can be
defined as loose, watery, and frequent stools. Diarrhea is reported
somewhat more frequently than constipation in PWS. Noninfectious
diarrhea can be caused by consumption of large amounts of poorly
absorbed dietary sweeteners (e.g, sorbitol or fructose) or fat substitutes
(olestra), use of antiabsorptive agents (e.g., orlistat), and food intolerance (e.g., lactose intolerance). Consumption of contaminated foods,
not uncommon in PWS due to the foraging behavior, enhances the
likelihood of acquiring infectious diarrhea. A careful history, examination of the stool and blood count, stool cultures (including cultures for
C. difficile, if indicated), and parasite studies (including giardia lamblia)
may be included in the evaluation.
Treatment of diarrhea is dependent upon the cause. Diarrhea, especially if copious, watery, and acidic, can cause perianal irritation, bleeding, and infection. These secondary conditions also require attention
and treatment.
Rectal ulcers may occur as a result of a regional skin picking sometimes termed “rectal digging.”14,38,143 This behavior is often exacerbated
by rectal irritation from constipation, diarrhea, or large stools. Symptoms may include mucoid rectal discharge, bloody stools, constipation,
rectal pain, abdominal pain, and tenesmus. Behavioral and possibly
psychotropic agent therapies are the recommended therapy for skin
picking (see Chapter 12). Stool softeners and treatment of constipation
and other contributory factors are also necessary to avoid further rectal
irritation.
Treatment of bowel disorders in individuals with PWS often requires
ongoing specialized treatment and monitoring. A multidisciplinary
approach is often necessary to optimize therapy.
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
Other Gastrointestinal Organs
No intrinsic structural or functional abnormalities in pancreatic exocrine or endocrine function have been identified in PWS. Disordered
serum levels of pancreatic secretions (e.g., insulin, pancreatic polypeptide) have been reported, as discussed elsewhere, but are not postulated to be due to primary pancreatic disease.
Nonalcoholic fatty liver disease (NAFLD) is a condition that typically occurs in obese individuals, particularly those with insulin
resistance, characterized by lipid accumulation in the liver.67 NAFLD
may progress through the stages of fat accumulation (steatosis), fibrosis
and inflammatory necrosis (nonalcoholic steatohepatitis), cirrhosis,
and liver failure. The first stage is fairly common in the general obese
population; subsequent progression is less common, but NAFLD is a
major cause of nonalcoholic liver failure in the overall population.
Diagnostic signs include elevated liver enzymes, liver enlargement,
and ultrasound evidence of steatosis. Hepatic steatosis has been
occasionally reported in cases of PWS,99,203 but the overall frequency is
not known. The treatment of NAFLD has not yet been delineated,
although metformin may have beneficial effects in the early stages of
disease.112
There are two case reports of childhood liver tumor in PWS, an
adenoma and a hepatoblastoma.95,180 It is not known whether these
were specific or chance associations.
Obesity and Nutrition
Definitions
Obesity or overweight is both a major feature of PWS and a burgeoning
problem in the non-PWS population. However, the recognition, diagnosis, and characteristics of obesity in PWS are very different from
virtually every other population. In addition, while the terms obesity
and overweight may be interchangeable in the general population, this
may not the case in PWS. This is not merely a semantic argument; distinguishing obesity from overweight may have important pathophysiologic and treatment implications for PWS.
The derivation of the word obesity is somewhat obscure. An online
dictionary of etymology (www.etymonline.com) has the following
listing:
obesity—1611, from Fr. obésité, from L. obesitas “fatness, corpulence,” from
obesus “that has eaten itself fat,” pp. of obdere “to eat all over, devour,” from ob
“over” + edere “eat.” The adj. obese is attested from 1651.
Other sources trace the word to ob (Eng: toward) ese (Ger: eating).
In modern medical terminology, obesity is often defined as a condition characterized by excessive body fat. While some definitions include
reference to overweight resulting from excess body fat, a more standard
scientific definition refers to an excess proportion of fat to nonfat mass.
This latter definition is probably most relevant to PWS.
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In normal human physiology and with usual diet composition, as
weight is gained, fat and nonfat (bone, muscle, water) mass increase in
a nearly linear relationship, with fat increasing at a faster rate than
nonfat mass.75 This “companionship of lean and fat”75 holds for a
variety of human conditions in which total body weight is altered,
including diabetes mellitus, anorexia nervosa, and “normal” obesity. In
an underweight individual, there is a relatively higher proportion of
lean mass. As body weight increases, the ratio of fat to nonfat mass
gradually increases, but both compartments increase in a linearly correlated fashion.
Because of this relationship, a ratio of weight to height provides a
reasonable estimate of total body fat, with weight (kg) divided by
height squared (m2), also known as body mass index (BMI), providing
the best approximation of more direct measures of body fat (see Body
Composition section in this chapter). For non-PWS populations, BMI
provides a convenient noninvasive indicator of body fat. As defined by
the Centers for Disease Control, obesity in adults is equated with a BMI
of ≥25. However, it is possible to have a BMI in the obese range without
actually being obese, as in the case of a body builder who has increased
muscle mass.
Since the proportions of body fat to height change during human
growth, childhood overweight is defined as a BMI ≥95th percentile as
compared with the age-/sex-related norms; obesity is not defined by
BMI alone. As with adults, overweight usually but not always equates
with obesity. For instance, athletic adolescent males may have increased
muscle mass, decreased fat mass, and a relatively high BMI.
PWS is one of the few conditions in which the companionship
between fat and lean does not hold. Forbes noted that while individuals
with a number of conditions showed a linear, superimposable relationship of lean mass and weight, individuals with PWS were clear outliers,
with a marked deficit in lean mass for weight.75,76 Other studies have
shown an excess of body fat in individuals with PWS, including underweight infants.20,40,54,55
Therefore, in the natural history of PWS, while overweight invariably equates to obesity, normal and underweight are also accompanied
by increased body fat. At least by the definition of increased fat to lean,
all individuals with PWS, regardless of weight, may be considered
obese. Distinction of obesity and overweight (total body mass) may be
important in terms of defining related morbidity risks and treatment.
In addition, total fat mass and fat distribution may have different
pathophysiologic implications from obesity and overweight.
Pathogenesis
Given the above discussion, the pathogenesis of the increased fat mass
in PWS can be separated into two considerations, which may or may
not be related to one another:
1. What causes the apparent violation of the “companionship rule”;
i.e., why does fat mass increase in an abnormal proportion to lean
mass as weight increases?
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
2. What causes the apparently insatiable appetite and the consequent
unlimited weight (primarily fat) gain?
Knowledge of the pathogenesis of these conditions could be crucial to
designing adequate treatment protocols.
The inappropriate proportion of fat to nonfat mass probably
begins in utero and is accompanied by an absolute deficit in muscle and
bone mass. This could result from either (1) inappropriate preferential
shuttling of nutrients into fat, thereby causing a deficit in lean
(bone and muscle) mass, and/or (2) inappropriately low utilization of
nutrients by bone and/or muscle, leading to a default deposition
of fat.
The mechanisms by which the human body normally shuttles
ingested substrate (glucose, amino acids, fatty acids) into fat, muscle,
and bone have not been completely defined72,98,115 and a discussion of
this topic is beyond the scope of this chapter. There is evidence that
hormones and neuropeptides that may regulate appetite (e.g., leptin,
neuropeptide-Y (NPY), adiponectin, Agouti-related protein) may also
affect substrate partitioning98,115; however, much of the data has been
collected in rodents and may not apply directly to humans. In addition,
no specific defects in the physiology or action of these substances have
been reported in PWS, and none are coded within the PWS gene region.
Therefore, it is not known at this time whether the primary body composition abnormality in PWS is excess lipogenesis, decreased formation
of muscle and/or bone, or a concomitant dysregulation of both fat and
nonfat mass accretion.
The propensity for insatiable appetite and weight gain in PWS is
likewise not completely understood. Normal eating behavior has been
separated into three components: (1) an initial, relatively acute “drive
to eat,” or hunger; (2) an immediate postmeal feeling of fullness, or
satiety; and (3) a longer-lasting feeling of satisfaction, or satiation. The
control mechanisms for each of these stages are likely to be different.
On a theoretical basis, environmental stimuli and voluntary control are
more likely to influence hunger, whereas satiety and satiation may be
more dependent on intrinsic physiologic control. Studies indicate that
the primary deficit in PWS involves the third stage, satiation.131
Satiation may be controlled by endogenous appetite suppressants
and stimulants (orexins). Theoretically, the balance between these two
components is maintained by peripheral metabolic and/or neurogenic
signals. Many of the characterized appetite-regulatory pathways in
rodents and humans have been localized to the arcuate nucleus of the
hypothalamus. A primary hypothalamic defect has been postulated
to drive the hyperphagia in PWS, although no relevant functional or
structural abnormalities have been identified thus far.81,82,85,86 The possibility exists that the primary disorder may involve a defect in peripheral satiety signaling, perhaps related to the defective nutrient cycling
and body composition abnormality. This latter model would agree with
the clinical observation that the eating behavior in PWS more closely
resembles nutritional deprivation or starvation rather than normal
hunger.103,127
165
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
As of this writing, the study of appetite regulatory peptides in the
general population and in PWS is actively developing.50,56,199,201 The following list summarizes current knowledge of several postulated appetite regulatory peptides in relation to PWS. In general, the current
model of appetite regulation includes peptides generated within the
gastrointestinal system or body tissues that are released into the bloodstream (endocrine) or nervous system (neurocrine). These peptides
then feed back to specific receptors in the hypothalamus, resulting in
generation of signaling within the central nervous system and back to
the body tissues.
1. Cholecystokinin (CCK)
CCK is produced by the endocrine I cells in the duodenum and jejunum
in response to fat, amino acids, and gastric acid. Actions include stimulation of pancreatic enzyme secretion, gallbladder contraction, intestinal motility, insulin secretion, and pancreatic polypeptide secretion.
CCK delays gastric emptying and inhibits release of gastric acid. In the
brain, high concentrations of CCK are present in the cerebral cortex.
CCK is postulated to be responsible for initiating satiety during a
meal.201 In PWS, fasting levels of CCK are normal but unlike in nonPWS controls, fasting CCK is not correlated with free fatty acid levels.31
In response to a protein meal, CCK levels rise normally in individuals
with PWS.183
2. Pancreatic Polypeptides
The pancreatic polypeptides PP, PYY (peptide YY), and NPY (neuropeptide Y) are produced in the pancreatic islets of Langerhans (PP), the
large and small bowel (PYY), and peptidergic neurons of the stomach,
small intestine, and central nervous system (NPY). PP secretion is primarily stimulated by protein intake and cholinergic activity. PYY secretion is stimulated by mixed meals and oleic acid. NPY functions as
a neurotransmitter, with high concentrations in the arcuate nucleus
of the hypothalamus. PP and PYY are postulated to play a role in
satiety.
PP secretion in response to a protein meal has been reported to be
deficient in PWS.183,209,210 Short-term infusion of PP was initially reported
to cause a mild inhibition of food intake in females with PWS13; however,
a more detailed investigation indicated no effect.208
PYY levels have been reported to be low in non-PWS obese individuals, and PYY infusion causes a reduction in food intake.9 PYY levels are
reportedly low in PWS29; however, infusion studies have not been
reported.
NPY activity in the hypothalamus is postulated to stimulate food
intake.199 Hypothalamic NPY neurons appear to be normal in PWS.85
Serum levels of NPY are reported to be low-normal in adults with PWS
and do not change with GH therapy.108,109
3. Hypocretins (orexins)
Hypocretins are neurocrine peptides that are postulated to stimulate
feeding. Hypocretin-containing neurons in the lateral hypothalamus
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
are stimulated in response to hypoglycemia. Hypocretins are also
postulated to play roles in regulating energy expenditure and sleep/
wake cycles. In a study of hypocretin levels in relation to sleep disorders,142 cerebrospinal fluid hypocretin levels were found to be normal
in a 16-year-old with PWS. However, cerebrospinal fluid hypocretin
levels were reported to be low in four patients with PWS, in association
with daytime sleepiness.154
4. Agouti-Gene-Related Protein (AGRP)
AGRP production is co-localized with NPY in the hypothalamus. AGRP
stimulates food intake by inhibiting the actions of melanocortin, an
anorexigenic neurocrine peptide. AGRP expression was reported to be
decreased in the neonatal mouse model of PWS, in which there is
failure to gain weight (as with human PWS).80 However, AGRP neurons
appear to be normal in older individuals with PWS.85
5. Ghrelin
Ghrelin is a peptide released from cells in the stomach. The normal
function of ghrelin is not completely defined. In both rodents and
humans, serum ghrelin levels rise progressively during fasting and it
is postulated that ghrelin provides a signal to initiate food intake. In
agreement with this theory, pharmacologic administration of ghrelin to
mice results in increased food intake. However, the ghrelin knockout
(deficient) mouse has no apparent defect in appetite or any other body
function.178 Recent studies indicate that the hyperphagic effect of exogenously administered ghrelin in mice is mediated by NPY/AGRP
neurons.44
Serum ghrelin levels have been reported to be elevated in individuals
with PWS29,48,51,84,92,109 and are postulated to contribute to the hyperphagia. However, examination of the data reveals that levels are not
increased in all individuals with PWS (although hyperphagia is virtually universal) and mean levels are not significantly different from
normal in some studies.16 In addition, serum ghrelin levels appear to
decrease appropriately in response to meals and somatostatin administration in PWS.16,93 Therefore, as of this writing, the role of ghrelin in
PWS pathophysiology is not known.
6. Opioids (endorphins)
Opioid peptides produced within the central nervous system function
as neurotransmitters. In some cases, opioids may enhance intake of
foods, particularly sugary foods, perhaps by inducing positive sensations.199 Opioids have been postulated to play a role in various types
of eating disorders, including PWS.116 However, serum levels of betaendorphin were found to be normal in children with PWS,138 and
administration of opioid inhibitors had no effect on food intake.207,211
7. Leptin
Leptin is produced by fat and appears to signal adequacy of energy
storage back to the brain.26,37,39,41,132 Except in those conditions involving
genetic defects in leptin or leptin receptor expression, serum leptin
167
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
levels correlate directly with body fat.202 In cases of genetic defects in
leptin synthesis, the hyperphagia and other physiologic abnormalities
are alleviated by leptin administration. However, it is not clear at this
point whether pharmacologic administration of leptin to normal obese
individuals, who have high leptin levels, will lead to significantly
decreased food intake. It has been postulated that leptin functions primarily to signal energy deficiency rather than adequacy.
In PWS, leptin levels are increased and appear to be directly correlated with body fat.26,37,39,158 Molecular defects of the leptin gene have
not been identified in PWS.33 Growth hormone therapy may decrease
leptin levels in PWS; this effect is probably related to decreased absolute body fat.59,111,148,205
Energy Expenditure
Previous studies have described alterations in metabolic rate in individuals with PWS. Schoeller et al.169 noted problems with use of common
mathematical formulae to predict the basal metabolic rate (BMR) in
adults with PWS and advocated use of the Cunningham BMR formula
to adjust for the deficit in lean mass (FFM). Subsequent studies100,188
have demonstrated a low basal metabolic rate with varied interpretation of data dependent upon the technique of body composition analysis. However, although resting energy expenditure may be normal or
near-normal for lean mass, lean mass is deficient, leading to deficient
expenditure for total body mass.12,82,169
Despite differences in body composition, energy expenditure during
physical activity is similar to that of controls151,152 when corrected for
lean mass. However, individuals with PWS are less active than controls.49,189 The combination of diminished BMR and activity level necessitates lower caloric intake or a significant increase in physical activity
to avoid excessive weight gain.
Associated Morbidities
Body fat itself is rarely a direct cause of morbidity or mortality. Fat
embolism is an example of direct fat-related morbidity, but this condition is not reported to occur with increased frequency in PWS. In PWS,
the increased proportion of fat to lean mass (regardless of weight) is
largely the result of decreased muscle mass. The resultant hypotonia is
a major contributor to morbidity and mortality, as discussed in previous sections. As body weight increases above normal in PWS, the fat
mass itself becomes problematic.
Body fat can contribute indirectly to pathophysiology in two ways:
(1) complications due to a mass effect, i.e., in morbidly obese individuals, and (2) via metabolic complications related to fat.
The detrimental effects of excess body mass are well recognized. In
particular, increased fat is associated with respiratory impairment and
obstructive apnea. The sheer weight of excess fat in the presence of
low muscle mass also contributes to impaired physical mobility and
difficulty with daily tasks. Many adults with PWS adopt a typical
hypotonic posturing, with both arms folded across the upper abdomen,
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
while others become wheelchair-dependent in young adult life.
Increased fat mass may also theoretically exacerbate scoliosis and fragility fractures involving weight-bearing bones and joints (vertebrae
and hips), but, on the other hand, increased weight may augment bone
mineral density, as shown in non-PWS populations.129
Metabolic effects of increased body fat have been well defined in the
general population. In non-PWS children, early puberty (particularly
adrenarche),163 accelerated linear growth, and advanced bone age can
occur; final adult height is usually not adversely affected despite the
accelerated physical development. Adrenarche is the portion of sexual
development characterized by increased production of adrenal androgen precursors, which, in the peripheral tissues, are converted to testosterone and dihydrotestosterone. In normal puberty, adrenarche is
responsible for secondary sexual hair growth in females; the effect of
adrenarche is usually less notable in boys due to testicular production
of testosterone. The hormones produced during adrenarche also cause
acceleration of bone growth and epiphyseal closure. The physiologic
control of the timing of adrenarche has not been defined; however,
insulin resistance and hyperinsulinemia are associated with earlier
onset.
In children with PWS, premature adrenarche occurs in a relatively
small subset of cases121,126,167 and is manifested by early (before age 8 to
9 years) appearance of pubic hair. Anecdotal experience suggests that
the frequency of premature adrenarche is less than might be expected
in a similarly overweight non-PWS population. In affected children,
the increased linear growth rate due to adrenarche often replicates a
normal, non-PWS growth rate (which is actually accelerated for PWS).
Unfortunately, the end result is often extreme short stature due to premature epiphyseal closure, which is quite different from the normal
stature attained by non-PWS children with obesity-related premature
adrenarche. Therefore, “idiopathic” premature adrenarche cannot be
considered to be a benign condition in PWS.
In older children, adolescents, and adults, obesity can lead to metabolic syndrome, also known as dysmetabolic or insulin-resistance syndrome (defined by various criteria, but generally including insulin
resistance, overweight/obesity, dyslipidemia, and hypertension; all
associated with increased cardiovascular risk), polycystic ovary syndrome, and Type 2 diabetes mellitus.58 In non-PWS populations, insulin
resistance and consequent morbidities have been specifically associated with increased abdominal visceral fat (as opposed to subcutaneous fat).
Glucose intolerance and Type 2 (also known as non-insulindependent) diabetes mellitus (T2DM) can occur in patients with
PWS.27,42,78,91,113,123,150,162,170,172,203 The usual case of T2DM in PWS is indistinguishable from non-PWS obesity-related diabetes, which is occurring with increasing frequency worldwide.198 Unlike Down and Turner
syndromes, there does not appear to be any unique risk for Type 1
(insulin-dependent) diabetes mellitus (T1DM) in PWS. In addition,
no specific metabolic abnormalities have been identified in PWS to
169
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
suggest a unique predisposition to T2DM except for obesity.21,136 A
reduced amount of insulin receptors was noted in one report, but the
clinical significance of this finding is uncertain.120
Recent data indicate that individuals with PWS may have a lower
risk for insulin resistance and T2DM than would be expected based on
the degree of overweight. Average fasting insulin levels are reported
to be low in children and adults with PWS and there is a relative lack
of clinical signs consistent with insulin resistance,57,111,145,156,181,206 although
some reports have found elevated fasting insulin,125,155 and others have
reported elevated fasting but decreased 2-hour postprandial insulin.128
However, the bulk of evidence suggests that insulin levels are relatively
low in most individuals with PWS, arguing against an increased frequency of insulin resistance. In addition, serum levels of adiponectin,
a protein secreted by adipocytes that is thought to increase insulin
sensitivity, are unexpectedly high in PWS,110 whereas low levels are
usually observed in non-PWS patients with obesity and insulin
resistance.
In non-PWS individuals, insulin resistance syndromes and T2DM are
part of a spectrum of disorders related to increased body fat and, in
particular, intra-abdominal visceral fat73,165 (as distinguished from subcutaneous fat). Lipid deposition in muscle and other body tissues may
also be contributory.114 However, in obese individuals with PWS, subcutaneous but not visceral fat has been found to be increased83,182; the
mechanisms for this occurrence have not been defined. In addition,
visceral fat characteristics for individuals with PWS and insulin resistance have not yet been reported.
Monitoring for signs and symptoms of insulin resistance and T2DM
should be a routine element of care for all individuals with PWS. Some
cases of T2DM may present with the classic symptoms of diabetes
mellitus: polyuria, polydipsia, and, in some cases, unexpected weight
loss despite continued hyperphagia. Ketoacidosis, obtundation, and
disordered consciousness may occur in the most severe cases.203
However, most individuals with insulin resistance or T2DM will be
asymptomatic. A classic, but not universal, physical sign of insulin
resistance is acanthosis nigricans: hyperpigmented, velvet-textured
skin in the nuchal, axillary, inguinal, and other folds of the body
thought to be due to direct or indirect effects of hyperinsulinemia on
keratinocytes.184
Individuals suspected of having insulin resistance should be screened
for associated morbidities, including dyslipidemia (fasting lipid panel)
and hypertension. Diagnosis of impaired glucose tolerance (IGT) and
T2DM should be made according to criteria of the American Diabetes
Association2:
1. Symptoms of diabetes plus casual plasma glucose concentration
≥200 mg/dl (11.1 mmol/l). Casual is defined as any time of day
without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
or
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake
for at least 8 hours.
or
3. Two-hour post-load glucose ≥200 mg/dl (11.1 mmol/l) during an
OGTT. The test should be performed as described by the World
Health Organization (WHO), using a glucose load containing the
equivalent of 75-g anhydrous glucose dissolved in water.
Since criteria 1 and 3 do not require an elevated fasting glucose, and a
2-hour oral glucose tolerance test may not always be feasible, some
practitioners utilize a random glycated hemoglobin or hemoglobin A1c
measurement to screen for clinically significant glucose intolerance and
diabetes mellitus.
Treatment
Nutritional management of PWS can be separated into four major areas
of concern:
1.
2.
3.
4.
Control of under- and overweight
Optimization and conservation of lean mass
Special nutritional considerations
Treatment of obesity-related morbidities
Evolving clinical needs for the individual with PWS requires adaptation of nutritional support. During infancy, diminished muscle tone
affects the volume of caloric intake during feedings. A variety of techniques are available for nutritional support of the infant with PWS
including adaptive feeding bottles and nipples (e.g., Haberman feeder,
cleft palate nurser, adaptive nipples), thickening agents (Thick-It,
cereal), formula concentration, and nasogastric tubes. The feeding
therapy utilized is determined by the adequacy of swallowing skills,
and nutritional status.
Nasogastric and gastrostomy feedings are commonly used to meet
the nutritional needs of infants with PWS. Gavranich et al.,79 reported
use of tube feedings for a mean of 8.6 weeks among 67% of infants with
PWS in New South Wales. Since gastrointestinal absorption and motility are essentially normal, intravenous total parenteral nutrition is
usually not required. In infants receiving feedings primarily through a
non-oral route, oral feedings as tolerated and non-nutritive sucking
should be continued to encourage development of oromotor strength
and coordination.
Intake parameters during infancy can be patterned along guidelines
from the Nutrition Committee of the American Academy of Pediatrics.47 During the first 6 months of life, breast milk and infant formula
should serve as the primary nutritional source and should be given in
usual amounts. Solids are generally introduced at 5 to 6 months of age
and advanced in texture, dependent upon oral motor skills. Highercalorie solids, desserts, and juices are commonly avoided. Through
close monitoring of growth data over the first 2 years, oral intake can
be appropriately adjusted to maintain weight for height between the
171
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
25th and 80th percentiles. Caloric restriction under the guidance of an
experienced nutritionist or other health care provider is required, with
supplementation of deficient vitamins and minerals, if weight gain
becomes excessive.
Nutritional strategies beyond the toddler years focus on avoidance
of overweight. Limited studies106,159 have evaluated the caloric requirements for individuals with PWS. Weight maintenance has been reported
with intakes of 8 to 11 kcal/cm/day (non-PWS children require 11–
14 kcal/cm/day; cm = height); weight loss has been documented with
intakes of 7 kcal/cm/day. Sample calorie guidelines, adapted from
guidelines published by PWSA (USA) 17 are listed in Table 6.1. It should
be noted that while these guidelines are based on logical criteria, there
are no prospective data regarding efficacy. In addition, these guidelines
may be excessive for children who are unusually inactive and, conversely, inadequate for children with PWS receiving growth hormone
therapy.
Similar guidelines have not been specifically formulated for adolescents and adults with PWS, although a general recommendation has
been 800 to 1,000 kcal/day for weight loss. These calorie guidelines are
a significant reduction from usual food intake in the general population; therefore, the individual with PWS will probably need to have
different food preparation and provision from the rest of the
household.
A typical approach to a calorie-restricted weight control treatment
plan is to introduce a “balanced” calorie reduction, with maintenance
of the usual carbohydrate-protein-fat proportions (i.e., 60%-15%-25%,
respectively). Emphasis on low-glycemic-index carbohydrates (i.e.,
slowly-absorbed complex carbohydrates rather than, for instance, high
sugar foods) may also reduce insulin secretion, facilitate optimal nutrient utilization and have a positive effect on satiety,135 although these
effects have not been studied in individuals with PWS.
Adherence to a calorie-restricted diet requires intensive and continuous monitoring of intake and regular dietary counseling, including
analysis of food histories and attention to possible associated nutrient
Table 6.1. Sample Calorie Guidelines
Age (yr)
Female
3
5
7
9
Average Height (cm)
Weight Maintenance
(kcal/d)
Weight Loss
(kcal/d)
89
102
112
135
700–980
800–1120
880–1232
1060–1484
630
720
790
954
94
107
119
122
740–1036
840–1176
940–1316
960–1344
660
760
845
864
Male
3
5
7
9
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
deficiencies. Behavioral aspects of this plan require attention to all
potential sources for intake including cafeterias, school buses, classroom activities (“life skills”), vending machine access, neighbors, and
convenience stores as well as home access (e.g., pantry, garbage cans,
refrigerator, tabletop). Locks on kitchen doors and refrigerators are
often recommended elements of this plan. More detailed discussions
of behavioral and environmental management strategies appear elsewhere (see Chapters 12 and 18).
There is no doubt that total calorie restriction will achieve weight
maintenance or loss if completely implemented; however, it remains
unresolved as to whether this approach is justified in view of the physiology. As mentioned above, there is growing consensus that the food
foraging and apparently insatiable appetite in PWS may be triggered
by internal mechanisms that more closely resemble true starvation than
non-PWS pre-meal hunger or eating behavior. If this is true, then the
intentional restriction of all intake could have detrimental effects on
overall behavior and well-being and may, in fact, augment foraging
and food-sneaking behavior. This hypothesis has not been tested,
although it appears to hold some validity on review of anecdotal patient
experience.
An equally important issue relates to adverse effects on body composition. Although increased body fat and overweight is a major visible
morbidity in PWS, a more crucial functional morbidity is the lack of
lean mass. In non-PWS individuals, induction of an energy deficit (e.g.,
fasting, total calorie restriction) and weight loss using a balanced nutrient intake results in loss of not only fat mass, but also lean mass. In
addition, the lower the total calorie intake, the higher the proportion
of lean mass lost. In non-PWS individuals, excess body fat will provide
a relative protection against loss of lean mass (i.e., thinner individuals
lose proportionately more lean mass than obese individuals during
weight loss).77
As stated by Dr. Gilbert Forbes, a pioneer in this field of research,
“There is no level of reduced energy intake that will completely spare
LBM [lean body mass] when significant amounts of body weight are
lost.”75 In individuals with PWS, where total lean mass is deficient even
in the presence of overweight, there is no reason to suspect that a
balanced calorie restriction diet will result in preservation of absolute
lean mass.
However, lean mass can be at least relatively preserved during
calorie deficit by preferentially preserving protein intake. The initial
observations of this phenomenon preceded the currently popular lowcarbohydrate, increased protein diets.75 In a short-term metabolic unit
study in four patients with PWS, a protein-sparing (1.5 gm of meat
protein per kg body weight), ketogenic, modified fast preserved positive nitrogen balance and lean body mass in the presence of significant
weight reduction.15 A similar nutritional approach in an obese ventilator-dependent adolescent with PWS apparently facilitated weight management and weaning from the ventilator.45
In addition to potential effects on preservation of lean mass, protein
may have a greater positive effect on satiety than carbohydrates or fat,
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
as demonstrated in both short- and long-term human studies.5,25
Although this effect has not been investigated in individuals with PWS,
it was postulated to occur in outpatient follow-up of patients involved
in the previously mentioned study using a protein-sparing fast.15
A ketogenic protein-sparing fast is probably not practical for most
individuals with PWS. However, several other approaches to highprotein, lower carbohydrate meal planning are available. Popular diets
using this approach typically result in 28% to 35% calories from protein,
8% to 40% from carbohydrate, and the remainder from fat.5 One of the
authors (PDKL) has prescribed modified lower-carbohydrate, lower-fat
guidelines in his PWS clinics for several years, an approach which is
similar to other, perhaps more stringent regimens.5,146,147 The basic fivestep approach is as follows: (1) elimination of sugar and all packaged
foods containing >5 g sugar per serving, (2) limitation of complex carbohydrates to one to two servings three times daily, with one serving =
15 gm of carbohydrate, (3) avoidance of fried and fatty foods, (4) encouragement of lean protein intake, and (5) provision of “free foods”—i.e.,
carb-free, low-fat, low-calorie—for ad lib snacking and/or foraging. In
addition, an exercise guideline of 30 minutes sustained activity, three to
five times weekly is recommended. This regimen is provided as a onepage guideline and reviewed during clinic visits. For most individuals,
adherence to this simple plan results in a substantial reduction in total
calories. This approach has the advantages of being easy to learn
(requires teaching of food label readings and basic carbohydrate counting), relatively straightforward implementation, and possible integration into usual household eating patterns. More structured dietary
regimens can be added to this basic program for individual patients.
Whatever dietary approach to weight control is taken, it is important
that it be logical, consistent, easily implemented, emphasized at each
clinic visit, and carefully monitored. Modifications should be made for
individual patients, and in children developmental changes should be
taken into account.
Pharmacologic agents for weight management should be considered
as adjuncts and not primary treatment modalities. None of the appetite
suppressant or antiabsorptive agents marketed for obesity treatment
have shown efficacy in PWS, and systematic studies have not been
published. Some of the psychotropic agents commonly used in PWS
have been anecdotally reported to control food-foraging behavior, but
exacerbation of overeating has also been observed.118 Anecdotal reports
indicate that growth hormone therapy may have a beneficial effect on
eating behavior, but this has not been demonstrable in objective studies.
In a short-term uncontrolled trial, the anti-epileptic medication, topiramate, was reported to improve eating and other behaviors in seven
patients with PWS, resulting in weight loss in three175; however, several
of the subjects were on concomitant medications and the overall results
were not entirely conclusive.
Personal experience and one report42 indicate that metformin may
have efficacy for weight control in PWS when coupled with dietary
management, particularly with carbohydrate limitation. Similar results
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
have been reported in treatment of non-PWS obesity.6,146,147 The
mechanism(s) of action for metformin in weight management have not
been completely elucidated, although an anorectic effect has been demonstrated in animal studies.112
Surgical options for weight management are not generally recommended in PWS. Bariatric surgery causes weight loss through either a
diminished capacity for food intake and/or via reduced digestion and
absorption of food. In non-PWS obesity, studies in adolescents and
adults show efficacy in promoting weight loss, although surgical risks,
gastrointestinal problems, and malabsorption are a concern.71
Experience with bariatric surgery in PWS has been less encouraging,
as summarized in Table 6.2, although relatively long-term success has
been reported in selected patients.
There is no apparent effect of bariatric surgery on hyperphagia in
PWS. Therefore, the need for dietary intervention and monitoring is
not eliminated. Over the long-term, weight gain may recur after the
patient develops compensatory dietary strategies. At the current time,
bariatric surgery should be considered only in severe cases in which
serious obesity-related morbidities are present and rapid weight loss is
considered to be potentially beneficial.
Special Nutritional Considerations
Vitamin and mineral supplementation is highly recommended for
individuals with PWS and particularly for those on a balanced, calorierestriction diet. For example, the sample calorie guidelines from PWSA
(USA)17 listed in Table 6.1 are deficient in calcium, iron, vitamin D,
vitamin E, biotin, pantothenic acid, magnesium, zinc, and copper;
multivitamin and mineral supplementation is recommended in the
publication. In addition, many individuals with PWS have limited
sun exposure, especially those affected with hypopigmentation. Since
a large proportion of the body stores of vitamin D are synthesized in
response to sunlight, lack of sun exposure can result in vitamin D deficiency and an increased risk for osteoporosis.
As a general rule, it is recommended that all patients with PWS
receive daily multivitamin and mineral supplementation in consideration of their individualized meal plan and sun exposure. An over-thecounter preparation may be adequate for many patients. Others may
require additional monitored supplementation with calcium, trace
minerals, and vitamins. Trace mineral, iron, and fat-soluble vitamin
supplementation should be carefully monitored to avoid overload.
Obesity-Related Morbidities
Premature Adrenarche
In children without PWS, premature adrenarche is usually a benign
condition that does not require specific therapy; indeed, specific therapies have not been proven to have efficacy.163 In some cases, premature
adrenarche may be associated with early central puberty, which may
require treatment. As mentioned previously, premature adrenarche in
175
Type of Surgery
Gastroplasty
91% Gastric bypass
9% Gastroplasty
Vagotomy
Jejunoileal bypass
Biliopancreatic
diversion
Reference
Soper et al.
(1975)176
Anderson et al.
(1980)4
Fonkalsrud
and Bray
(1981)74
Touquet et al.
(1983)185
LaurentJacard et al.
(1991)124
3
1
1
11
No. of
Patients
7
Table 6.2. Bariatric Surgery in Prader-Willi Syndrome
27.6 yrs
24 yrs
17 yrs
13 yrs
Median
Age
15 yrs
84.5 kg
181 kg
120 kg
85 kg
Median
Weight
92.5 kg
Significant
wt loss
1st year,
followed by
wt gain (2½–
6 yrs)
62 kg (1 yr)
29 kg initial
wt loss,
followed by
20 kg gain
Success
Rate
43%?
• Diarrhea
• Vitamin D, vitamin B12,
folate, and iron deficiency
• Postoperative wound
infection
• DVT/pulmonary
embolus
• 4–5 stools/day
20-kg weight gain
• 54% required revision
due to inadequate wt loss
• 1 (9%) wound infection
• 1 dumping/diarrhea
• 1 death from
uncontrolled wt gain
Complications
57% required revisions
due to inadequate
weight (wt) loss
176
A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
Vertical banded
gastroplasty
Laparoscopic
adjustable gastric
band
Biliopancreatic
diversion
Biliopancreatic
diversion
95% gastrectomy
with Roux-en-Y,
hypocaloric diet
Roux-en-Y gastric
bypass
Dousei et al.
(1992)53
Chelala et
al. (1997)43
Grugni et al.
(2000)88
Marinari et al.
(2001)139
Braghetto et al.
(2003)19
Kobayashi
et al.
(2003)117
1
1
15
1
1
1
30 yrs
15 yrs
21 yrs
24 yrs
?
21 yrs
54-kg
weight loss
over 18 mos,
improved
lipid profile
70 kg weight
loss over 1 yr;
BMI = 30
BMI = 57.7
146 kg
56%–59% wt
loss at 2–3 yrs,
then
regained
10%–20% of
wt lost
Initial wt
loss, but wt
gain without
restriction
Initial
improved
DM control
127 kg
80 kg
?
57.4 kg
No complications
No surgical complications
reported
2 deaths from unrelated
causes
(no vitamin levels or bone
density data provided)
Diarrhea, severe
osteopenia, anemia,
hypoproteinemia
Death 45 days
postoperatively from GI
bleeding
Short-term wt loss
followed by break of
staple line and wt gain
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
177
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
children with PWS is not a benign condition since it is associated with
severe short stature and an inadequate increase in height velocity.126,167
Although obesity is thought to be pathogenetic for this condition, there
is no evidence that intensive weight control after onset will slow the
progress of the adrenarche. Prevention of predisposing factors for
premature adrenarche via weight management beginning in very
early childhood is the best recommendation at this point. In cases
where the process has already started, growth hormone therapy should
be considered even if current height is normal in order to optimize final
adult height.
Insulin Resistance and Type 2 Diabetes Mellitus
The treatment of insulin resistance and T2DM in PWS should follow
current standard-of-care guidelines for these conditions in the
non-PWS population. A comprehensive discussion of this topic is
beyond the scope of this chapter; the reader is referred to the current
literature and healthcare organizations for more detailed protocols
(e.g., American Diabetes Association, American Association of Clinical
Endocrinologists).
In general, the first-line approach should include diet and exercise,
as described above for treatment of obesity and overweight; in milder
cases, these therapies may lead to complete resolution of the disorder.
Metformin should be considered a first-line pharmacotherapy for
insulin resistance, especially if T2DM is present.42,112 Insulin may be
necessary in cases where there is evidence of insulin deficiency (ketoacidosis, unexplained weight loss) but should be avoided in all other
cases since it may augment increases in body fat. Sulfonylureas and
PPAR-agonists also have a tendency to increase body fat, and the efficacy of these agents in individuals with PWS and T2DM has not been
shown. The authors’ anecdotal experience suggests that diet, exercise,
and metformin are sufficient for treatment of most individuals with
PWS and insulin resistance and/or T2DM.
Monitoring of patients with insulin resistance and T2DM should
include periodic evaluation of fasting lipid profiles and blood pressure.
Fasting insulin levels can be checked periodically, but the clinical utility
of this measurement, which can be highly variable, is not defined.
Clinically, weight, calculated body mass index, waist circumference,
and status of acanthosis nigricans (if present) can be useful.
Individuals treated with metformin should have routine annual
monitoring of liver and kidney function tests; an elevated serum creatinine level is a contraindication to therapy. With T2DM, routine home
monitoring of fasting and postprandial glucose levels and periodic
glycated hemoglobin measurements are necessary, with an optimal
goal of achieving normal levels for both parameters.
There have been surprisingly few reports of diabetes-related complications in PWS.8,192 However, individuals with diabetes mellitus should
be routinely monitored for evidence of retinopathy, nephropathy,
hypertension, and cardiovascular disease, with institution of appropriate therapy as needed as per general standard-of-care practice
guidelines.
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
Measurement of Body Composition
The measurement and monitoring of body composition has become an
essential element in clinical research and management of individuals
with PWS. In particular, body composition measurements may be used
to diagnose decreased bone mineral density (osteopenia, osteoporosis)
and monitor changes in total body fat and nonfat mass.
Anthropometry
Anthropometry refers to body measurements, such as length or height,
weight, circumferences, and skinfold thickness. Although anthropometric techniques (weight-for-height indices, skinfold thickness, waistto-hip ratio) have been used for many years to indirectly estimate body
composition, these techniques are less commonly used for that purpose
today. Instead, if detailed body composition analysis is needed, more
sophisticated models and techniques are used, as discussed below.
Height growth is an essential feature of human development and
should be measured for all children at regular intervals. The measurements should be plotted to the nearest fractional age on charts compiled from the background normal population. Such charts are available
for the U.S. pediatric population from the U.S. Centers for Disease
Control (www.cdc.gov). Standards for most other industrialized countries are available. Children under 2 years of age should be measured
using recumbent length, which is the basis for these standards. Height
velocity charts are also available. Procedures for accurate measurement
and calculation of height and velocity are also described on the CDC
Web site.
Height growth is basically a measure of long bone (leg, spine) growth,
which in turn is dependent on a number of genetic, hormonal, structural, and mechanical factors. Abnormal height growth in children can
be the first sign of a systemic abnormality. As mentioned previously,
height growth in children with PWS is highly variable but usually
abnormally low starting at or before the toddler stage. As shown in
several population studies, the average final adult height in PWS is at
approximately 2 standard deviations below the mean for the background population.1,22,36,97,123,149 Scoliosis, if present, may also account
for loss of height growth.
Weight is basically a measure of total body mass, regardless of composition. As a stand-alone measurement, it has little intrinsic utility,
even if plotted on normative curves. However, the clinical value of a
weight measurement is increased when analyzed in conjunction with
height, that is, in determination of weight-for-height or body mass
index. Assuming that fat and lean mass are present in a predictable
proportion (see previous discussion regarding “companionship rule”
above), these ratios can provide a measure of body fatness (normative
charts available on www.cdc.gov). However, in conditions where there
is an excess proportion of lean mass (e.g., body building) or deficient
lean mass/excess fat mass (e.g., PWS), these ratios do not provide an
accurate estimation of body fat.
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
Anthropometric measurements for head circumference, hand
and foot length, and other body parts have been published for
PWS28,32,34–36,65,141,196 (see Appendix C). Head circumference measurements are primarily used as an indicator of brain growth in infants
and toddlers under 3 years of age. Careful monitoring of head growth
is also important for detection of craniosynostosis, premature closure
of the cranial sutures resulting in severe neurologic sequelae. One
such case in PWS has been published,66 and the authors are aware of
other cases.
Waist circumference and waist to hip circumference ratios have been
used to indicate visceral fat and consequent risks for T2DM and cardiovascular disease in non-PWS adults. However, this correlation is
likely to be less reliable in PWS since visceral fat may not be
increased.
Skinfold thicknesses, measured using calipers at selected body sites,
are sometimes used to estimate body fat and non-fat mass. Skinfold
thickness is basically a measure of subcutaneous fat. Using assumptions and validated algorithms regarding the proportions of subcutaneous fat to other body compartments, fat and lean mass can be estimated.
Although skinfold thickness measurements have been used in several
key studies of PWS,30,54,96 inter-observer variability and lack of validated disease-specific (including PWS) standards and algorithms are
major limitations to routine clinical use.193
Body Composition Modeling
The first step in determining body composition is to select a model that
provides clinically relevant measurements (Figure 6.3). The most
extreme form of body composition analysis, elemental or chemical
Figure 6.3. Multicompartment models of body composition. A. Basic 2compartment model, weight = Fat + FFM (fat-free mass). B. Water, protein, and
mineral subcompartments of FFM. C. Body cell mass and extracellular water
and solids subcompartments of FFM. D. 3-compartment dual-energy X-ray
absorptiometry (DXA) model.
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
analysis after ashing, is primarily of research interest since it is not
feasible in an individual living organism. Elemental analysis can be
also performed in vivo using isotope counting and neutron activation
methods62; these measurements currently have limited clinical utility
and will not be discussed.
The simplest clinically useful model of body composition, the 2compartment (2-C) model, divides total body mass or weight (Wt) into
fat mass (FM) and fat-free mass (FFM). Body fatness, in turn, can be
defined as the FM/Wt ratio, expressed as a percentage. The basic 2-C
model requires only one measurement to be made and is the easiest to
use when the assessment of body fatness is the primary aim.
More detailed clinical models,194,195 particularly for considering issues
related to nutrition or growth, separate the FFM into components, creating a multicompartment model (Figure 6.3). A useful multicompartment model separates FFM into water and/or protein (muscle) and
mineral (bone) subcomponents. Direct assay of FFM components is
difficult but has been facilitated by recently developed imaging techniques. These sophisticated techniques, such as dual-energy X-ray
absorptiometry (DXA), computed tomography (CT), and magnetic
resonance imaging (MRI), allow us to view the components of the
living body.52
In the following sections of this chapter, the various methods that
are available will be described in the context of their application in 2-,
3-, and 4-compartment models of body composition.
Methods Based on the 2-Compartment (2-C) Model
Underwater Weighing: For the 2-C model, Wt = FM + FFM, and VolTB =
VolFM + VolFFM (Total body volume = FM + FFM volumes). An accurate
measurement of body weight is relatively easy to achieve, i.e., using a
weight scale; the measurement of body volume is more challenging.
The classic technique of measuring body volume, underwater weighing (UWW, or hydrostatic weighing) relies on Archimedes’ principle,
which states that a body immersed in a fluid is buoyed up by a force
equal to the weight of the displaced fluid. The procedure involves
measuring body weight while totally submerged underwater, after
exhalation of air from the lungs. The body volume is calculated by
subtracting the underwater weight from the regularly measured body
weight, the weight differential being equal to the weight of displaced
water, and dividing the difference by the density of water. This number
is adjusted for the measured residual lung volume.
The density of the body (rTB) is the ratio of body weight (Wt) to body
volume (VolTB). The classic UWW relationship between body fatness
(%FM) and body density (rTB) for a 2-compartment model is
%FM = 100 ¥ {(k1/rTB) + k2}
where the constants (k1, k2) are determined by the values selected for
rFM and rFFM (densities of the fat and fat-free mass).24,173 The density of
fat can be assumed to be constant (0. 9004 g/cc), whereas the density
of FFM is not constant, changes with growth,134 and is altered by diseases and medications. Since body water is the major contributor to the
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
mass and volume of the FFM, changes in the relative water content
(hydration) will have significant effects on rFFM. Other components of
the FFM can also change, but these have a secondary impact compared
with hydration.
For short-term longitudinal studies in healthy subjects, using ageand gender-adjusted constants, the 2-C model is adequate for the
assessment of changes in body fatness. However, it does not provide
information about components of the FFM.
Air-Displacement Plethysmography: There can be several reasons why
the underwater weighing technique cannot be used, e. g., lack of necessary equipment, fear of water, difficulty breathing underwater, too
buoyant to be easily submerged. An alternative technique called airdisplacement plethysmography (ADP) can also be used to measure
body volume. The advantage of ADP is that the problems related to
water are eliminated, although the subject still needs to wear a tightfitting bathing suit and cap to cover scalp hair. The objective is to
determine the volume of air that is displaced by the subject’s body.68,134
At present, there are only two commercial ADP instruments available
(BODPOD for adults and PEAPOD for infants, Life Measurements Inc.,
Concord, Calif.).
The ADP technique is based on Boyle’s Law for gases: pressure multiplied by volume is constant if temperature does not change. Poisson’s
Law for gases is also used in order to adjust for the subject’s breathing
(heated moist air coming from the lungs) and for the isothermal effects
of air in contact with the subject’s skin and body hair.
For the BODPOD measurement, the subject sits on a bench in a small
test chamber that is about the size of a telephone booth. This chamber
is connected via a diaphragm to a reference chamber behind the bench.
The door (which has a large window) is closed, the diaphragm is oscillated at a low frequency, and the pressure difference between the two
chambers is measured. The BODPOD instrument also has a built-in
spirometer system that can be used to measure the subject’s residual
lung volume. It should be noted that without preliminary training, the
spirometer procedure can be difficult for some subjects to perform
correctly.
ADP estimates of body volume are highly correlated with those for
UWW, and the two results are virtually interchangeable for healthy
adults.68 Additional studies with children may be needed, especially
where body composition may be abnormal. However, it is reasonable
to expect that the ADP technology may replace the underwater weighing technique for 2-C analysis in adult and pediatric populations.
Total Body Water and Potassium: Two alternate methods can be used in
a 2-C model to estimate body fatness by measuring body water and
cellular components of the FFM. The body composition parameters
that are measured for these methods are total body water (TBW) or
total body potassium (TBK), respectively.60,62
For these two assays, the simple 2-C equations for body fatness are
as follows:
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
%FMTBW = 100 ¥ (Wt - TBW/k3)
%FMTBK = 100 ¥ (Wt - TBK/k4)
where the values for k3 and k4 are assumed to be relatively constant at
a given age for a healthy subject. However, during infancy and childhood, the relative hydration and potassium content of the total FFM
are not constant, and they may also be altered by disease and/or medications.60 That is, the same limitations that were possible for the 2-C
UWW or ADP models are also present for the 2-C TBW and TBK
models. This is an inherent limitation of the 2-C model and not the
methods. An advantage of the TBW and TBK assays, compared with
UWW or ADP, is that these assays provide useful information on their
own about the composition of FFM.
For the TBW assay, the subject drinks a small amount of isotopelabeled (non-radioactive) water. Several hours later, a body fluid sample
(blood, urine, or saliva) is collected and stored for later analysis using
isotope-ratio mass spectroscopy (MS) or Fourier-transformed infrared
spectroscopy (FT-IRS). Since the amount of the tracer given to the
subject is known, and its concentration in the water part of the fluid
sample is measured, the total volume of the dilution space can be easily
calculated.168 The value for the conversion constant (k3) that is used
most often is 0.732 for older children and adults, gradually increasing
to 0.83 for infants. That is, FFM contains, on average, about 73.2% water
for healthy children and adolescents. This percentage, however, may
be altered with diseases, such as severe malnutrition or edema, and by
some drugs. A clear advantage of the TBW technique is that bulky
instrumentation is not needed at the times of isotope administration
and sample collection, thus making it a suitable choice for field studies.
The MS or FT-IRS analysis could be performed immediately, but the
usual practice is to collect multiple samples for batched analysis, thus
the TBW results are often delayed until some time after the actual
procedure.
The results of the TBK assay, on the other hand, can be obtained
immediately. This assay takes advantage of a natural signal that is
being constantly emitted from the potassium in the human body. A
small fraction of natural potassium is radioactive (40K), emitting characteristic gamma rays (1.46 MeV) at the rate of about 200 gammas per
minute per gram of potassium. This signal can be detected external to
the body using a whole-body counter,63 usually a whole-room shielded
counting chamber. Based on numerous studies over the past 40
years, the values for the conversion constant (k4) are estimated at 59 to
61 mEq/kg for adult females and 62 to 64 mEq/kg for adult males. For
infants, the ratio is reduced to ~43 mEq/kg because of increased hydration.60,61 A major limitation with this assay is that the measurement
instruments are not portable, and the number of available instruments
and facilities is very limited. However, it is well recognized that the
TBK assay is the best choice for monitoring body cell mass (BCM), the
active metabolizing tissues of the FFM.60 In many diseases, knowledge
of the patient’s BCM status has a higher priority than knowledge of
body fatness.
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
Bioelectrical Impedance: The bioelectrical techniques for assaying body
composition were developed as alternatives to the isotope dilution
assay of total body water. The attractiveness of this technology is that
the instruments are small in size, relatively inexpensive, don’t require
extensive operator training, and the results are immediately available.
The principle of the bioelectrical impedance technique is that the body
has general electrical properties, which primarily reflect the volume of
the FFM and its electrolyte content.90 Three approaches have been
developed for human use: (1) single frequency (50 kHz) bioelectrical
impedance analysis (BIA), (2) multifrequency (5–1000 kHz) bioelectrical impedance spectroscopy (BIS), and (3) total body electrical conductivity (TOBEC).
For the BIA and BIS procedures, pairs of electrodes are attached at
the hand and foot. A weak electrical current is passed between the
electrodes, and resistance (R) and reactance (Xc) are measured. The BIA
assay uses a single frequency (50 kHz), while the BIS technique varies
the frequency (5–1000 kHz). The basic BIA and BIS theory results in the
assumption that the Ht2/R ratio is directly proportional to TBW or
FFM.10 Some BIA instruments have been designed to measure only the
upper body (electrodes placed on the hands) or lower body (subject
stands in the electrodes), while other investigators have chosen to
perform segmental BIA measurements (placing multiple electrodes at
many sites on the body).
There are at least 30 single-frequency BIA devices commercially
available. Unfortunately, there are almost an equal number of algorithms to choose from for the calculation of TBW, FFM, or %FM. Furthermore, some investigators have suggested that disease-specific
calibrations of BIA should be used.191 Although this approach may, at
first, appear attractive, this type of “work around” simply avoids the
more difficult issues related to the limited accuracy of the basic BIA
theory and algorithms.
For the total body electrical conductivity (TOBEC) assay, no electrodes are placed on the body. Instead, the body passes through a large
diameter electrical coil. The free charge particles in the body will
attempt to align with the external magnetic field within the bore of the
coil, causing a small measured perturbation in the coil current. The
procedure takes only a few minutes to perform, and can be repeated
as frequently as needed without risk to the subject.
Similar to the BIA and BIS assays, the TOBEC technique is a secondary assay, which means that the measured value (called the TOBEC
number) must be calibrated with a more direct assay of FFM or TBW.
A limitation with the TOBEC instrument is that it is very large compared with the BIA and BIS devices; hence it is not portable, and its
initial cost is substantially higher. Thus, the number of TOBEC instruments worldwide is extremely limited, as with those based on the TBK
technique.
Methods Based on the 3-Compartment (3-C) Model
Body Density + TBW: As pointed out for the 2-C density models (UWW
and ADP), the major limitation was the assumption that TBW was a
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
fixed percentage of the total FFM. This constraint can be overcome by
using a 3-compartment (3-C) density model where the measurement of
TBW is included. In this case, the %FM equation becomes:
%FM = 100 ¥ {(2.118rTB) - 0.78 TBW/Wt - 1.354}
where the density of body fat and solids are 0. 9004 g/cc and 1.565 g/cc,
respectively. The advantage of this model is that the hydration state of
the FFM can be variable, without introducing additional error in the
estimate for body fatness. The disadvantage is that two assays (UWW
or ADP and TBW) are needed, which increases the complexity and
decreases feasibility of the procedure.
Dual-Energy X-ray Absorptiometry: Absorptiometric techniques were
developed in the 1960s to examine bone because of the concerns that
astronauts would experience significant bone loss during space flight.
Over the last 40 years, significant advances have been made with this
technology, evolving into the current technique, called dual-energy Xray absorptiometry (DXA).62 DXA assays of the hip and spine have
become the clinical standards for the assessment of bone mineral
density, used to screen for the increased risk of bone fractures, especially in postmenopausal women. In addition, a whole body DXA can
be obtained in approximately 3 minutes with a very low total radiation
dose (<10 mSv).
During a DXA procedure, the subject lies supine on the exam table,
clothed but with removal of metal objects. An X-ray scanning arm
passes over the selected body parts or the whole body. The X-rays are
attenuated during passage through body tissues. The net signal is
detected, converted into pixels, and analyzed using algorithms. For
diagnosis and monitoring of osteoporosis, the scan is usually limited
to the hip and/or lumbar vertebral spine, which are sites that are prone
to osteoporotic fragility fractures. For more complete body composition
analysis, a whole body scan is obtained.
In order for DXA to provide a quantitative measure of bone, the
physics requires that the density of the overlying soft tissue must be
known. This is accomplished by analyzing the nonbone pixels in the
image next to the bone-containing pixels for their relative fat-to-lean
content. Thus, a whole-body DXA scan can be used to produce a quasi3-compartment (3-C) model: bone mineral content (BMC), fat mass
(FM), and nonbone lean tissue mass (LTM). The sum of the bonecontaining pixels provides a measurement called the bone area (BA),
and areal bone mineral density (BMD) is defined as BMC/BA. It is
to be noted that the DXA-derived BMD (g/cm2) value is not true
bone density (g/cm3) but a projection of the total body mass onto a 2dimensional or plainer image of the body.
A clear advantage of whole-body DXA is that the body scan image
is divided into 10 general regions (head, arms, legs, trunk, pelvic, spine,
etc.) with BMC, BMD, fat, and LTM calculated for each region. Thus,
not only can the body FM be examined but also its regional distribution. Although this information is useful, it does not, for example, distinguish between subcutaneous fat and visceral fat stores in the body.
185
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
Methods Based on Body Imaging Techniques
To obtain precise body composition information, anatomical imaging
techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), are used. The CT technique uses collimated
beams of X-rays that are passed through the body, and an array of
detectors is positioned on the opposite side of the body to detect the
transmitted signal.62 The X-ray source and detector assembly are rotated
as a single unit around the body, and the data are collected and reconstructed to generate a cross-sectional image or “slice” of the body for
each rotation. The physics of the CT procedure makes it a quantitative
assay, i.e., the relative density (g/cc) of each pixel in the cross-sectional
image can be obtained. Thus, anatomical regions such as the subcutaneous adipose tissue (SAT) layer, muscle, skin, internal organs, bone,
and visceral fat deposits (VAT) can be identified. A disadvantage
with routine CT imaging is that the radiation exposure is higher than
that needed for a DXA scan, and whole body or extensive regional
scans are not feasible.23 The image requirements for a clinical CT
scan can be relaxed when it is used for body composition analysis,
such as for determination of VAT and SAT, which reduces the dose
significantly.177
Magnetic resonance imaging (MRI) also provides internal images of
the body, which tend to be superior in anatomical quality to those
obtained using CT. One can easily identify the subcutaneous and visceral fat areas, for example, in an abdominal MRI image. However, the
quantitative quality of the MRI image is much less than that obtained
with the CT scan, and a whole body MRI can take up to 10 times longer
to perform than a DXA. On the other hand, the MRI technique has
several advantages, including the ability to distinguish VAT and SAT,
and the system can be tuned to respond specifically to lipids contained
within the lean tissues.137,166 This may help to better understand the
association of excess adiposity with some chronic diseases, such as
T2DM.114
Methods Selection
The pathogenesis of PWS involves alterations in body composition that
are atypical for human physiology and pathophysiology. In particular,
there is an inherent increase in fat mass that is disproportionate to lean
mass regardless of weight. The distribution of this fat mass could be
relevant to defining cardiovascular risk. Lean mass is extremely deficient, as reflected in the hypotonia and decreased spontaneous activity.
Finally, bone mineral density tends to be low, particularly in older
individuals with PWS, increasing the risks for osteoporosis and fragility fractures. Given these considerations, body composition monitoring
is an important element of clinical care for individuals with PWS.
However, the selection of methods can be confusing.
As discussed above, there are a number of techniques that can be
used to examine human body composition,62 each with its own sets of
advantages and disadvantages. Two-compartment (fat, nonfat) and 3compartment (fat, bone, nonbone lean) models have been the most
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
popular and clinically feasible. Higher-level models may provide a
more complete picture of body composition, but multiple assays are
required, some of which are not routinely found in most institutions.
In terms of 2-compartment models, the BIA technique has become
widely available partly because it is relatively easy to perform, requires
minimum investment, and is portable (for field studies or bedside use).
Unfortunately, the body composition results are often not much better
than those obtained using anthropometric measurements, such as body
mass index calculations or skinfold measurements.
For more accurate 2-compartment modeling, air displacement plethysmography (i.e., using the BODPOD instrument) offers an attractive
alternative to the more difficult underwater weighing technique.68
However, the feasibility of this procedure in PWS has not been tested. In
addition, although the methods for 2-compartment modeling are
designed to measure fat-free mass (with fat mass calculated as the residual), they have the disadvantage of not providing additional information
regarding the nonfat component (i.e., bone and nonbone lean mass).
Table 6.3 summarizes key considerations for body composition measurement methods, classified by the measured component. Costs are
based on 2004 U.S. estimates. Precision and accuracy of each method
are listed, as well as the minimal detectable change.
For practical purposes, the DXA procedure has become the reference
method for the clinical assessment of bone mineral. This clinical acceptance of DXA, and its accessibility at many institutions, is also driving
the use of this technique as a reference for the measurement of body
fatness and lean mass. For patients with PWS, the DXA procedure has
the additional advantages of rapidity, minimal patient cooperation
requirements, and provision of measurements for all three clinically
relevant body compartments. The 1% to 3% analytical precision of the
DXA method allows detection of relatively small longitudinal changes
in bone, fat, and nonbone lean tissues. However, there are significant
differences in the calculation of %FM by DXA versus more sophisticated techniques; therefore, further improvements in DXA may be
needed before a consensus can be reached186 regarding the utility of
DXA in estimating FM and nonbone lean mass. In addition, DXA methodologies differ according to manufacturers; results are not directly
interchangeable; and pediatric, age-related, and ethnic normal ranges
have not been widely accepted.9,62,122,200A minor disadvantage of DXA
is that an exposure to X-rays is required; however, the dose is very
small (>10 mSv) and carries minimal risk. From a practical standpoint,
the DXA platform has body weight limitations; scans cannot be performed on individuals over 300 pounds on some commonly used DXA
machines.
Single-slice abdominal CT and MRI methods are excellent choices
when information about the distribution of body fat in the abdominal
region is important. This information could have relevance to defining
cardiovascular risk; however, these methods have not yet been validated for monitoring of individual patients, PWS or otherwise. In addition, these methods do not provide information about whole body
tissue status.
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A.O. Scheimann, P.D.K. Lee, and K.J. Ellis
Table 6.3. Comparison of Body Composition Methodologies
Measured
Compartment
Total Body
Water
Method
Deuterium
dilutiona
BIA/BISb
QMRc
Instrument
Cost (US$)
25–70 K
Procedure
Charge (US$)
50–100
Precision
%
1–2
Accuracy
%
2–3
MDCi
Amt. (%)
2 L (5)
3–7 K
100 K
30
—
2–4
1
3–7
—
4 L (10)
1 L (3)
Fat-Free Mass
UWWd
ADPe
BIA/BIS
DXAf
25–35 K
30–80 K
3–7 K
125 K
45
45
30
150
1–2
1–2
2–4
2
2–3
2–3
2–8
1–2
2 kg (4)
2 kg (4)
4 kg (7)
1 kg (2)
Fat Mass
DXA
CTg
MRIh
125 K
800 K
1500 K
150
350
600
2–3
3–4
3–4
3–5
3–4
3–4
2 kg (11)
— (10)
— (10)
Bone Mineral
Density
DXA
125 K
150
1
2–3
CT
800 K
175
1
1
0.04 g/cm2
(4)j
1.2 mg/cc
(1)k
a
Requires baseline body fluid sample, such as plasma, and 2–4 hours post-dose sample. Can be assayed using
infrared spectroscopy or mass spec.; results are not “immediate,” 2nd assay must be delayed 15–30 days to allow
for initial dose to clear. Use of 18O instead of deuterium results in 5–10-fold increase in assay cost.
b
Single (BIA) and multifrequency (BIS) bioelectrical impedance analysis. At least 30 commercial instruments, with
equal number of prediction equations. Can be repeated as needed.
c
Quantitative magnetic resonance has only been used with small animals, but has been shown to be more accurate
than dilution method and can be repeated as needed without harm. Magnetic field strength is about 1/200 of routine
MRI instruments.
d
Underwater weighing, requires subject to be totally submerged in water while air is exhaled from lungs. Classic
method in use for more than 50 years, limited use for infants and older adults.
e
Air-displacement plethysmography replaces underwater weighing method. Easily tolerated by subjects, can be
repeated as frequently as needed, and both adult and infant-sized instruments are available.
f
Dual-energy X-ray absorptiometry. Often considered as “gold standard” for in vivo bone mineral measurement.
Gives regional information about body fat distribution.
g
Computed tomography gives information about internal distribution of fat. Most frequently used to assay subcutaneous and visceral fat components of abdominal fat. Scan times in seconds, but frequency of repeat scans is
limited by the radiation dose.
h
Magnetic resonance imaging gives information and image of internal distribution of fat. Can be repeated as
needed, but requires substantially longer time than CT.
i
Minimum detectable change (MDC) for an individual. Value in parenthesis is the change expressed as a percent
based on body composition of a 79-kg male with 25% fat. For CT and MRI, a 10% change in either fat subcompartment should be detectable.
j
Values are for areal bone mineral density; similar values for total body, spine, or hip DXA.
k
True density of bone, usually performed only for the spine.
In summary, with the various techniques that are available today, it
is possible to obtain an accurate in vivo assay of the human body and
to monitor the changes with growth or treatment of diseases. DXA is
currently the most useful procedure for assessment of body composition in individuals with PWS; however care should be exercised in the
proper interpretation of results.
Chapter 6 Gastrointestinal System, Obesity, and Body Composition
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